Dr Neil Henderson (Liver)

Title: Investigation of myofibroblast αv integrins as an anti-fibrotic target in biliary atresia and fibrosis

Project Start Date: 1 October 2014

Completion Date: 30 September 2017

Summary:

Biliary atresia is a devastating condition which causes inflammation and destruction of children’s bile ducts and can lead to biliary fibrosis (scarring of the liver), liver failure and death. When biliary fibrosis becomes severe, the liver begins to fail and currently our only available treatment for end-stage liver scarring is transplantation. However a shortage of donor organs means many patients die on the waiting list and patients undergoing liver transplantation have to take immune system suppressing drugs for the rest of their life. Therefore effective new treatments for biliary atresia and fibrosis are urgently required.

The mechanisms at the cellular and molecular level responsible for the development of liver scarring (fibrosis) in biliary atresia are not fully understood. Myofibroblasts are specialised cells within our liver that are the major source of scar tissue during biliary fibrosis. Dr Henderson and his team focused their research on myofibroblasts as potential targets to develop new treatments for biliary atresia and fibrosis.

Their initial approach was to explore the use of a new drug to block a specific molecule in myofibroblasts, to see if this reduced scar formation. Unfortunately this initial approach was not successful in stopping scar formation when the researchers tested it in myofibroblasts obtained from the liver of patients with biliary atresia, nor when tested in the liver of mice that the team used to replicate biliary atresia in a live research model.

However the researchers made an interesting observation. They noted that liver fibrosis caused by biliary atresia developed differently at the cellular and molecular level compared to fibrosis caused by other types of injury, such as for example caused by exposure to a toxic chemical agent. This seems to indicate that there are fundamental differences in the characteristics of the myofibroblast depending on what triggers the liver fibrosis. Indeed there has been ongoing debate in the hepatology field over the last 5-10 years as to whether a distinct, ‘biliary fibrosis-specific’ population of myofibroblasts exists – so-called portal fibroblasts, or whether biliary fibrosis is driven by the same cells that mediate other type of liver fibrosis.

To try to answer this key question the researchers decided to change approach. They used a cutting-edge technique called single cell RNA sequencing, which allows examination of gene expression levels in individual cells, rather than the traditional methods which generate an average gene profile across millions of cells. This new technique is powerful because it has allowed the researchers to identify, with an unprecedented level of detail, the key myofibroblasts that drive biliary and other type of liver fibrosis. Gaining this level of detail has allowed the researchers to start finding potential molecular targets in the myofibroblasts that could be used to develop new treatments for biliary atresia and liver cirrhosis.

The next steps for their research will involve testing these potential molecular targets in mice research models. If these pre-clinical studies are successful, this will help the researchers apply for further funding from major funding body bodies such as the Medical Research Council or the Wellcome Trust, both of which would greatly facilitate rapid translation of the newly identified therapeutic targets to the clinic.

Guts UK’s funding is enabling us to investigate a potential target to block liver scarring in patients with biliary atresia, and also other causes of biliary fibrosis, which will underpin the design of clinical trials. If successful, this would potentially represent a major step forward in the care of these patients as it could significantly reduce the need for liver transplantation.

Dr Neil Henderson

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